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Immune microenvironment plays a role in the development of lung cancer (LC). We hypothesized that immune profile of B and T cells may differ in tumors of LC patients with and without COPD and may also influence survival. Objectives: 1) To analyze levels of tertiary lymphoid structures (TLSs), B and T cells in tumor and non-tumor (control samples) lung specimens of LC patients with/without COPD and 2) to analyze the influence of those biological markers in the patients´10-year survival. TLSs (numbers and area), B (CD20), and T (CD3) cells were identified in both tumor and non-tumor specimens (thoracotomy) from 90 LC-COPD patients and 43 LC-only patients (immunohistochemistry). Survival was analyzed in all 133 patients. Immune profile in tumors of LC-COPD versus LC: The number of TLSs significantly decreased in tumors of LC-COPD compared to LC patients. No significant differences were observed in tumors between LC-COPD and LC for B or T cells. In tumors compared to non-tumor specimens, a significant rise in TLSs was observed in LC (numbers and area) and LC-COPD (area), T cell counts declined in tumors of LC, while B cell counts increased in tumors of both LC and LC-COPD patients. Survival: In LC-COPD patients: lower numbers of TLSs and greater numbers of B cells were associated with worse survival. In LC patients: lower levels of T cells were associated with longer survival rates. TLSs, B cells and T cells are differentially expressed in tumors of LC-COPD from that in LC-only patients. Method: FIS 18/00075 & CIBERES (FEDER, ISC-III), SEPAR 2018, unrestricted research grant from Menarini SA 2018.

Whether a deficiency in muscle repair and regeneration may exist in the lower limb muscles of COPD patients remains debatable. We hypothesized that the negative regulator myotastin may inhibit muscle regeneration potential in sarcopenic COPD patients. In vastus lateralis (VL) of control subjects and severe COPD patients with and without sarcopenia, satellite cells (SC) were identified (immunofluorescence, anti-Pax7 and anti-myf5): activated (Pax7+ and myf5+), quiescent/regenerative potential (Pax7+ and myf-5-), and total SC, nuclear activation (TUNEL assay), and muscle fiber type (morphometry, hybrid fibers), muscle damage, muscle regeneration markers (Pax7, myf-5, myogenin, and myoD), and myostatin levels were identified. Compared to control subjects and normal body composition COPD, in the VL of sarcopenic COPD patients, myostatin protein levels, activated SC, hybrid fibers, TUNEL-positive cells, internal nuclei, and total abnormal fraction were significantly increased, while quadriceps muscle strength, numbers of Pax7+ and myf-5- and slow- and fast-twitch muscle fiber areas decreased. In VL of sarcopenic and non-sarcopenic COPD patients, TUNEL-positive cell counts were greater, whereas expression of muscle regeneration markers was lower than in controls. Myostatin may have interfered with the process of muscle cell proliferation early on during the regeneration process, thus leading to poor muscle growth and development following injury in COPD patients with sarcopenia. This may be another relevant mechanism of muscle mass loss in COPD. Method: CIBERES, FIS 18/00075 (FEDER), SEPAR 2018, and unrestricted grant from Menarini SA 2018.

Skeletal muscle dysfunction is a common feature in COPD which is associated with intrinsic muscular abnormalities, but it is not known whether there is an easy way of predicting their presence in early stage of disease. Using a mouse model of cigarette smoke exposure, we tested the hypothesis that 31-phosphorus magnetic resonance spectroscopy allows us to early detect skeletal muscle bioenergetic deficit. We employed this technique to assess the rate of ATP synthesis, and characterized the concomitant mitochondrial dynamics patterns in skeletal. We specifically explored whether experimental COPD model may alter mitochondrial respiratory chain complexes in peripheral muscles. We evaluated citrate synthase (CtS) and cytochrome c oxidase (COX) enzyme activities in gastrocnemius of mice. We found that rate of muscle ATP synthesis was reduced in skeletal muscle of mice exposed to cigarette smoke. Furthermore, ATP synthesis rate was directly related to mitochondrial enzyme activity. Emphysematous mice showed a significant reduction in body weight gain and decreased activity of CtS/COX. Taken together, these data support the hypothesis that in early stage of lung disease we are able to detect a decreased skeletal muscle ATP synthesis, in part caused by low mitochondrial enzyme activity. These findings may prove relevant to predict the skeletal bioenergetic deficit presence in the early stage of the lung disease and thus be able to act preventively in the evolution of the disease, besides placing mitochondria as potential therapeutic target for the treatment of COPD comorbidities.